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      Application of CRISPR/Cas9-Based Gene Editing in HIV-1/AIDS Therapy

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          Abstract

          Despite the fact that great efforts have been made in the prevention and therapy of HIV-1 infection, HIV-1/AIDS remains a major threat to global human health. Highly active antiretroviral therapy (HAART) can suppress virus replication, but it cannot eradicate latent viral reservoirs in HIV-1/AIDS patients. Recently, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system has been engineered as an effective gene-editing technology with the potential to treat HIV-1/AIDS. It can be used to target cellular co-factors or HIV-1 genome to reduce HIV-1 infection and clear the provirus, as well as to induce transcriptional activation of latent virus in latent viral reservoirs for elimination. This versatile gene editing technology has been successfully applied to HIV-1/AIDS prevention and reduction in human cells and animal models. Here, we update the rapid progress of CRISPR/Cas9-based HIV-1/AIDS therapy research in recent years and discuss the limitations and future perspectives of its application.

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          Most cited references89

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          Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements.

          Prokaryotes contain short DN repeats known as CRISPR, recognizable by the regular spacing existing between the recurring units. They represent the most widely distributed family of repeats among prokaryotic genomes suggesting a biological function. The origin of the intervening sequences, at present unknown, could provide clues about their biological activities. Here we show that CRISPR spacers derive from preexisting sequences, either chromosomal or within transmissible genetic elements such as bacteriophages and conjugative plasmids. Remarkably, these extrachromosomal elements fail to infect the specific spacer-carrier strain, implying a relationship between CRISPR and immunity against targeted DNA. Bacteriophages and conjugative plasmids are involved in prokaryotic population control, evolution, and pathogenicity. All these biological traits could be influenced by the presence of specific spacers. CRISPR loci can be visualized as mosaics of a repeated unit, separated by sequences at some time present elsewhere in the cell.
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            Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

            The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
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              Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product.

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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                22 March 2019
                2019
                : 9
                : 69
                Affiliations
                [1] 1School of Basic Medical Sciences, Institute of Medical Virology, Wuhan University , Wuhan, China
                [2] 2Laboratory of Medical Virology, School of Medicine, Sun Yat-sen University , Guangzhou, China
                [3] 3Department of Veterinary Biosciences, Center for Retrovirus Research, Ohio State University , Columbus, OH, United States
                Author notes

                Edited by: Jean-Christophe Paillart, Université de Strasbourg, France

                Reviewed by: Christian Schwartz, Université de Strasbourg, France; Emiliano Ricci, Institut National de la Santé et de la Recherche Médicale (INSERM), France

                *Correspondence: Deyin Guo guodeyin@ 123456mail.sysu.edu.cnl

                This article was submitted to Virus and Host, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2019.00069
                6439341
                30968001
                f9f62b66-35d2-4a9c-9ef3-35a74d55cc91
                Copyright © 2019 Xiao, Guo and Chen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 January 2019
                : 04 March 2019
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 160, Pages: 15, Words: 13194
                Categories
                Cellular and Infection Microbiology
                Review

                Infectious disease & Microbiology
                hiv-1/aids,crispr/cas9,gene editing,host factors,latent viral reservoirs

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